University Of California At Davis

NIH Research Projects · FY 2026 · 2024-12

PROJECT SUMMARY Osteoporotic fractures due to age-associated bone loss impart tremendous economic burden and impair quality and longevity of life. There remains an undeniable need to identify mechanisms that underlie bone deterioration with age, for the targeted development of novel therapies that can reverse bone loss to improve bone quality, fracture resistance, and quality of life. Changes in bone mass during aging occur via dysregulated skeletal remodeling. Under healthy conditions, skeletal remodeling maintains healthy bone mass and biomechanical integrity. Homeostatic remodeling balances osteoclastic (OC) bone resorption and osteoblastic (OB) bone formation coordinated by osteocytes (OCYs). OCYs are terminally differentiated OBs embedded within the bony matrix that live for decades and are the most abundant cell type in bone. OCY hypoxia inducible factor (HIF) signaling is an obligate regulatory pathway in skeletal health and maintenance. HIFs are transcription factors composed of an oxygen-dependent α subunit (transcriptionally active isoforms: HIF-1α, HIF-2α) and constitutively stable ß subunit (HIF- ß). HIF-α isoforms stabilize under hypoxia and induce skeletal changes. Skeletal Hif2a expression increases with age, concomitant with senile osteoporosis, and heterozygous Hif2a depletion abrogates senile osteoporotic bone loss. Cellular senescence associates with age-induced osteoporotic bone loss. Senescence is characterized by irreversible growth arrest and secretion of pro-inflammatory and matrix-degrading factors, creating a toxic microenvironment that drives age-related tissue dysfunction. Hif2a levels increase with age, concomitant with expression of canonical senescence markers p16 (Cdkn2a) and p21 (Cdkn1a) in bone, suggesting mechanistic coupling between HIF-2α and cell senescence. Furthermore, HIF-2α can bind to hypoxia response elements (HREs) in p16 and p21 promoters and directly regulate their expression. While OCYs from aged mice express senescent markers, whether HIF- 2α controls OCY senescence is unknown. Our overall hypothesis is that HIF-2α expression increases with age in OCYs and directly contributes to age-induced osteoporosis by promoting senescence-associated gene expression. We will test this hypothesis by establishing the relationship between HIF-2α and senescent gene signatures in OCYs during skeletal aging (Aim 1) and demonstrate that OCY HIF-2α stabilization drives a senescent gene signature in OCYs using in vivo and in vitro approaches (Aim 2). Using micro-computed tomography, biomechanics, and histology, we will demonstrate that Hif2a deletion prevents age-related bone loss and preserves bone strength in mice (Aim 3). Our overall goal is to elucidate HIF-2α’s role in driving OCY senescence and osteoporosis, revealing novel targets that can be harnessed pharmaceutically to prevent age- induced senescent-related bone loss. This proposal describes a comprehensive research training plan, supported by innovative facilities at UC Davis that will foster my scientific and professional development toward my long-term goal of pursuing an academic research position.

NIH Research Projects · FY 2026 · 2024-12

Project Summary Iron-sulfur clusters are found in all kingdoms of life, used by nature for electron transfer, for performing highly specific organometallic chemistry in the biosynthesis of natural products, and for catalysis of challenging redox transformations of small molecules. Elucidating the mechanisms of these reactions is critical for understanding the fundamental biochemistry of these enzymes, which could inspire future drug and (bio)catalyst design. Spectroscopic techniques to probe enzymatic mechanisms and reactive intermediates under physiological conditions and in nondestructive manners are desired but can be difficult to achieve. Advanced electron paramagnetic resonance (EPR) and parahydrogen induced polarization (PHIP) nuclear magnetic resonance (NMR) techniques, along with appropriate isotopic labeling, will be utilized to study the mechanisms and reactive intermediates of several enzymes containing unique iron-sulfur clusters. Herein, three systems suitable for these techniques are discussed. The last step of biotin synthesis is catalyzed by BioB, where a radical S-adenosyl-L-methionine enzyme sacrificially uses a [2Fe-2S] auxiliary cluster for S-atom transfer. A new, “Type II” class of BioB has been recently discovered, utilizing an uncommon [4Fe-5S] auxiliary cluster that may not be destroyed during turnover, though the mechanism is unestablished. Advanced EPR studies with appropriate isotopic labeling will help characterize the paramagnetic intermediates, providing hypotheses for their structures in the absence of crystallographic data. NMR hyperpolarization techniques (PHIP) will be employed to study the H-cluster of [FeFe]-hydrogenase, where the Britt group’s abilities to isotope-edit the 13C, 15N, and 57Fe nuclei of the diiron subcluster is hypothesized to allow for polarization transfer from parahydrogen, demonstrating the utility of PHIP in studying enzymatic mechanisms. Signal enhancement will overcome NMR’s inherent low sensitivity and allow for site-specific characterization of the structure and dynamics of the H-cluster under physiological conditions. The FeMo cofocator (FeMoco) of nitrogenase uses “green” sources of H2 in the form of H+ and e− to catalyze the difficult reduction of nitrogen into ammonia, which is used as fertilizer. Despite herculean efforts to understand this mechanism, much of it remains unestablished; the structure of the substrate-bound species is widely debated, and even less is known about the mechanism after substrate binding. FeMoco also generates one equivalent of H2 per turnover, and the H2 release is thought to relate to N2 binding in a reversible fashion. Thus, it is hypothesized PHIP is a technique well suited for probing this mechanistic step. Polarization transfer to other magnetic nuclei including 15N is expected to add direct evidence regarding the binding mode of substrate in FeMoco. Alternative strategies involving the design of polarization transfer catalysts that can produce hyperpolarized nitrogenase substrates are also proposed. Expected outcomes of this research will add to the rich field of iron-sulfur biochemistry and provide new spectroscopic tools for studying enzymatic mechanisms under physiological conditions.

NIH Research Projects · FY 2026 · 2024-12

Abstract Axial psoriatic arthritis (AxPsA), that is psoriatic arthritis (PsA) with involvement of the joints and ligaments of the spine, is a sequel of chronic inflammation of the PsA disease process. The spectrum and nature of inflammation in AxPsA is not fully understood, and therefore the condition is often misdiagnosed or underdiagnosed. Current evidence suggests that axial entheseal soft-tissue-associated pathology is likely to be the dominant pathology in AxPsA, compared to osteitis in ankylosing spondylitis (AS). These soft tissues involved in PsA spinal pathology are relatively avascular structures compared with tissues such as the bone/synovium and are therefore a ‘blind spot’ for current imaging technology. Positron emission tomography (PET), as a molecular imaging modality, has potential to interrogate these tissues directly, however, it has not been exploited for this application, due to concerns associated with dose, spatial resolution and scan time. Recently, total-body PET/CT technology has been introduced that may address these concerns. Indeed, in our preliminary studies, we utilized this technology and visualized and quantified spinal enthesitis as a dominant pathology in majority of the evaluated study participants with PsA. Based on these observations, our central hypothesis is that TB-PET/CT measures will (1) offer a unique insight of the pathology of AxPsA in vivo, and (2) provide biomarkers that will associate with the total spinal inflammatory burden in PsA. To test this hypothesis, our study has two proposed aims. Our first aim will characterize the inflammatory pathologies underlying AxPsA in vivo. We will derive consolidated, whole-spine measures from TB- PET/CT, as surrogate, in vivo measures of inflammatory pathology and establish their discriminatory power against those derived from participants with AS. Our second aim will quantify the total spinal inflammatory load in AxPsA via TB-PET/CT, and compare it with standardized outcome measures and MRI evaluation of spinal pathology. This study will assess the performance of TB-PE/CT to identify pathologies associated with spinal inflammation in AxSpA, quantify the total spinal inflammatory load, and perform comparison of resulting metrics with those derived from participants with AS. If successful, this study will contribute novel, objective and quantifiable TB- PET/CT imaging metrics (biomarkers) of spinal inflammation in PsA. Data collected will provide robust sample size estimates and feasibility measures for informing future clinical studies (observational and interventional trials), using the proposed imaging measures as outcome or surrogate measures.

NIH Research Projects · FY 2026 · 2024-12

PROJECT SUMMARY / ABSTRACT Alzheimer’s Disease (AD) is a devastating condition that affects more than 6 million Americans, with a total annual cost >$300 billion estimated in 2022. Currently, there are few treatments to counteract or slow the progression of AD, with promising findings in mice generally failing to translate into successful therapies for patients. Monkey models may provide a more powerful translational model. This work proposes to characterize fully a monkey model of AD tau pathology by performing microscopic analyses on the brains of rhesus macaques I am currently behaviorally testing to characterize tau-based cognitive decline (R24AG073138). Previous work has targeted the highly vulnerable entorhinal cortex (ERC) for unilateral infusions of an adeno-associated virus (AAV) expressing a double tau mutation known to cause tau-related dementia in humans (P301L/S320F) and characterized neuropathology at 1.5, 3, and 6 months after viral infusion. This causes extensive and progressive neuroinflammation and tau-based neuropathology, including neurofibrillary tangles, in ERC and in hippocampal and neocortical targets of ERC. PET imaging in these monkeys displays robust tau expression. Biomarkers for neurodegeneration are elevated in serum and CSF relative to baseline levels. The progressive time course relative to the time of vector infusion is a great strength in terms of using this model for therapeutic development. These early studies demonstrated the potential for this model to replicate pathological features of AD in the monkey brain and to capture aspects of pathology that have not been well-modeled in rodents. The successful characterization of this model with cutting-edge scientific methods will result in a multi-faceted and highly validated rhesus monkey model of the tau-based degenerative phase of AD with unprecedented translational power for efficiently developing and testing therapeutics throughout the pathological process. To meet this critical need, this project pursues two Specific Aims: 1) This project performs comprehensive microscopic studies to determine the regional and laminar patterns of tau-based neuropathology and extent of neuronal loss within the ERC and hippocampus 12 months after AAV injection into ERC, as well as more distal neocortical sites. This project correlates the tau-based pathology, including neuronal death, with the behavioral data I am currently collecting from the same animals. 2) This project performs comprehensive microscopic studies to determine the regional and laminar patterns of synaptic and neuronal health within the ERC and hippocampus, as well as more distal neocortical sites. This project correlates synaptic and neuronal health, which is closely related to neuronal functionality, with the tau-based pathology described in Aim 1, as well as the behavioral data I am currently collecting. A particularly novel aspect of this project is the utilization of immediate and early genes (IEGs) to study the health of neural circuits in use by the animal when exposed to a novel environment immediately before perfusion. All microscopic analyses and behavioral correlations will be highly quantitative and rigorous, facilitating therapeutic development and correlation across prior datasets.

NIH Research Projects · FY 2026 · 2024-11

Summary/Abstract Air pollution studies reported positive associations with the risk to develop breast cancer. Noteworthy, a stronger association of breast cancer risk was found with traffic related air pollution (TRAP) and higher polycyclic aromatic hydrocarbons (PAHs) exposure. PAHs result from combustion processes and derive from various sources (e.g. indoor fireplaces, wildfires, and vehicular traffic). Importantly, a stronger association of breast cancer has been identified with high air pollution exposure among African American and Japanese American women living in urban areas and near major roads presenting implications for health disparities and environmental justice. TRAP is a major ambient source of PAH exposure. PAHs such as benzo[a]pyrene (BaP) have been identified as ligands of the aryl hydrocarbon receptor (AhR). Activation of the AhR signaling pathway via environmental pollutants has been associated with the development of breast cancer. In a recent study, we showed that inhibition of AhR activity suppressed the onset and growth of mammary tumors in mice. Numerous reports suggest the important role that AhR plays in malignancies such as breast cancer and consequently the AhR has emerged as an attractive target for new drugs in cancer therapy. Moreover, recent studies and preliminary data reveal that the tumor microenvironment plays an important role in tumor promotion and progression of breast cancer. Tumor associated myeloid cells (TAMCs) such as myeloid- derived suppressor cells (MDSCs) and tumor associated macrophages (TAMs) with immune-suppressive activity play a key role in the tumor microenvironment of developing breast tumors. Preliminary data indicate that activation of AhR after TRAP exposure promote growth of mammary tumors and the accumulation of TAMCs. How TRAP exposure and activation of AhR signaling affects the function and accumulation of TAMCs to generate a pro-tumorigenic microenvironment and mediates growth and progression of mammary tumors is of critical importance. The study hypothesis is that elevated risks for breast cancer associated with exposure to TRAP is mediated via AhR signaling and tumor promotion through a pro-tumorigenic microenvironment enabling progressive tumor growth and metastases. While AhR has been studied in breast cancer cells in vitro, it is not yet known whether it mediates the tumor promoting effects of TRAP in a pre-clinical mouse model. This study would allow us to elucidate the mechanisms how the AhR controls the tumor promoting features of TAMCs in the tumor microenvironment stimulated by TRAP exposure. This project has the potential for high impact by identifying environmental risk factors and finding new innovative therapies to intervene and mitigate the development of breast cancer especially for people at higher risk through environmental exposure to air pollutants. The overall aim of this study was also the topic of the NIEHS/NCI workshop in 2022, “Complex exposures in breast cancer: unraveling the role of environmental mixtures”.

NIH Research Projects · FY 2026 · 2024-11

The goal of this work is to prevent primary CMV infection through prophylactic passive vaccination with a highly potent CMV IL-10 neutralizing monoclonal antibody. The greatest risk of congenital cytomegalovirus (CMV) infection, in terms of both numbers of infections and severity of disease, follows from primary maternal infection during the first trimester of pregnancy. There is no vaccine to prevent congenital CMV disease, and treatment options are limited due to risk to the fetus. Previous CMV vaccine approaches have focused on eliciting neutralizing antibody responses against viral glycoproteins, similar to those observed following infection. Glycoprotein B (gB) has shown some efficacy in CMV seronegative women and is considered a leading vaccine antigen, as are members of the pentameric complex. However, it is not clear whether targeting CMV glycoproteins can ever be sufficient to prevent or reduce CMV transmission since natural immunity to CMV in immune-competent people appears only to protect against clinical disease—not against (super)infection. We propose to protect against CMV infection by instead targeting the CMV-encoded IL-10 (cmvIL-10) immunomodulatory gene using a highly potent neutralizing monoclonal antibody. We hypothesize that a highly potent CMV IL-10 neutralizing monoclonal antibody will provide significant protection from horizontal primary infection in a rhesus macaque model for CMV. Aim 1. Characterize and purify highly potent viral IL-10 neutralizing monoclonal antibodies. Our preliminary data using active vaccination showed that macaques with strong rhcmvIL-10 neutralizing antibody responses were significantly protected from horizontal RhCMV infection. We will use PBMC isolated from those protected macaques to select for B cell clones and use them to produce highly potent vIL-10 neutralizing antibodies. Aim 2. Test if viral IL-10 neutralization protects against primary RhCMV infection. Our previous work demonstrated that rhcmvIL-10 neutralizing antibodies elicited following vaccination with recombinant protein provided significant protection from horizontal transmission of RhCMV. In this aim, we will determine whether highly potent rhcmvIL-10 neutralizing monoclonal antibodies provide similar protection, either alone or in combination with anti-gB antibodies. Significance. Host immune evasion and modulation by CMV have hindered development of a vaccine to prevent infection. Targeting cmvIL-10, a key viral immunomodulatory protein, with neutralizing monoclonal antibodies will open a novel approach to preventing CMV disease that also has potential to impact our understanding of how to control other pathogens that manipulate host immunity.

NIH Research Projects · FY 2026 · 2024-11

PROJECT SUMMARY Activation, clonal expansion, and affinity maturation of antigen-specific B cells are considered the hallmarks of adaptive immunity; hence, the assessment of B cell responses is thought to provide correlates of immune protection. Antigen-specific B cell responses have traditionally been observed indirectly, by examining the serum antibody pool using ELISA, or in the case of influenza the hemagglutinin inhibition assay (HIA). Direct measurements of antibody-secreting cells have also been done using ELISPOT, or more recently by flow cytometry. However, there are currently no tools to assess the functionality of the non-antibody (Ab) secreting memory B cell (Bmem) pool. This is an important limitation as Bmem, more than the circulating Ab pool, contain cross-reactive and cross-protective cells that could respond to a challenge infection with a mutated pathogen variant, such as occurs during the seasonal yearly influenza surges. Knowing the extent to which Bmem cells exist and can bind to the original or emerging variants of a pathogen would greatly help, for example, with decisions about when to update vaccines to the circulating seasonal influenza or SARS-COV-2 strains. The primary objective of this proposal is to generate such a tool. Our recent work demonstrates the proof-of- concept that a simple microfluidic platform can capture the full avidity spectrum of antigen-specific B cells, and that the equilibrium binding avidity of the BCR correlates strongly with the binding affinity of the secreted antibody. We have dubbed this approach and technology the Shear-force Avidity-based Cell Selector (SACS). These findings provide the foundation of our central hypothesis: capture, separation, and quantification of peripheral B cells based on the force-dependent BCR binding avidity can be used as a measure of functional immune status. To test our hypothesis, and fully develop the SACS technology, the specific aims of this project are to: 1) enhance the design and optimize a microfluidic device with the capacity to capture and separate a complex pool of B cells based on BCR binding avidity to a defined antigen; and 2) characterize the relationship between binding avidity dynamics of influenza-specific peripheral B cells and immune status following influenza virus infection. Our platform will demonstrate the functionality of a rapid and easily adaptable system to evaluate the dynamics of the B cell response to influenza, but is completely adaptable to host of other pathogens such as SARS-Cov-2. Expected results would provide a new measurement platform (SACS) that would allow for the first time the rapid assessment of the range of functional BCR-antigen interaction strengths of individual B cells within the complex pools of peripheral B cells and B cell subsets to predict functional immunity.

NIH Research Projects · FY 2026 · 2024-11

PROJECT SUMMARY/ABSTRACT The gut microbiota antagonizes infection with enteric pathogens in a process termed colonization resistance. Short chain fatty acids are considered a key component of colonization resistance, however, despite decades of research, the mechanism(s) of how short chain fatty acids exert colonization resistance and impede pathogen growth are incompletely understood. One of the main challenges in defining the mechanisms of short chain fatty acid toxicity has been that many gut bacteria, including enteric pathogens are inherently resistant. Disentangling mechanisms of toxicity and resistance has proven to be a major challenge. We discovered that Yersinia enterocolitica, a common cause of foodborne illness, is exquisitely sensitive to propionate under specific in vitro conditions, while fully resistant in other conditions. We posit that this this curious observation poses a unique opportunity to discover mechanisms of short chain fatty acid toxicity, as well as mechanisms of resistance. Based on our preliminary studies, we propose that propionate is erroneously converted by acetate kinase (AckA) and phosphate acetyltransferase (Pta) to propionyl-CoA, thus ensnaring the CoA pool and impeding acetyl-CoA metabolism. We will test key aspects of our hypothesis in vitro and in mouse models of infection using a strategic combination of bacterial and host genetics, metabolomics, and transcriptomics. We will pursue the following specific aims: 1. Determine the mechanism of propionate- mediated toxicity, and 2. Investigate the molecular mechanism(s) underlying Y. enterocolitica resistance to propionate in vitro and in vivo. Successful completion of this work is expected to reveal a novel molecular mechanism of short chain fatty acid-mediated toxicity; since Pta and AckA are widespread in bacteria, this mechanism may be applicable to gut bacteria in general. As such, these studies will advance our mechanistic understanding of how colonization resistance is achieved by the gut microbiota, and how enteric pathogens such as Y. enterocolitica can overcome colonization resistance.

NIH Research Projects · FY 2024 · 2024-09

ABSTRACT Aging is associated with increased risk of developing atrial fibrillation (AF). While AF affects <0.2% of people under 49 years old, it occurs in ~6% of those over age 65 and ~9-17% in those over age 80. AF is associated with increased morbidity and mortality through stroke, myocardial infarction, and heart failure and is characterized by abnormal and rapid atrial electrical activity that arises due to adverse electrophysiological, Ca2+- handling, structural, and autonomic remodeling. Despite age being a risk factor for the development of AF, how natural age-associated remodeling makes the atria more susceptible to arrhythmias is not fully understood. An additional layer of complexity is derived from potential sex differences in etiology. While males develop AF at an earlier age, women with AF have worse symptoms, poor treatment outcomes and higher mortality. These differences in the disease state may be reflective of sex differences in baseline atrial electrophysiology and the age-associated remodeling that predisposes to AF. However, due to historic underrepresentation of females in scientific and preclinical studies, sex differences in atrial electrophysiology associated with natural aging are currently unclear. In line with the goals of the National Institute on Aging (NIA) to better understand the biology of aging and disparities in age-related disease, the aim of this R03 Small Research Grant is to investigate sex differences in atrial electrophysiological, structural, and autonomic remodeling in aging to determine how biological differences in healthy aging may be predictive of arrhythmia risk. To do this, we will use a translationally-relevant ‘middle-aged’ rabbit model that demonstrates age-associated changes that predispose to AF, but is a timepoint before late-stage remodeling. We will take an integrative approach performing functional in vivo, ex vivo and biochemical studies on 3-4 year old male and female rabbit hearts alongside complementary computational modeling. Aim 1 will examine sex-specific electrophysiological characteristics and arrhythmia susceptibility in the middle-aged atria through optical mapping, in vivo ECG recording, and quantification of protein expression and fibrosis. Aim 2 will examine changes in autonomic modulation in middle-age and its role in atrial arrhythmogenesis. Aim 3 will investigate ionic parameters that may predict arrhythmia risk. Together, these experiments will characterize electrophysiological and autonomic changes in aging, evaluate age- dependent arrhythmogenic mechanisms, and uncover novel predictive features underlying the transition from healthy aging to AF.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Medications for opioid use disorder (MOUD) can reduce overdose mortality risk, and emergency departments (EDs) have been urged to adopt policies and procedures to facilitate MOUD initiation for patients with untreated OUD. In California, major state policy initiatives have supported the dissemination of CA Bridge – an innovative ED-based substance use program emphasizing low-barrier, ED-initiated MOUD -- to most California EDs from 2018-2022. CA Bridge’s outreach and training has targeted vulnerable subpopulations, including Medicaid enrollees, non-White patients, and patients residing in rural areas. In response to the CDC’s call for rigorous evaluations of policies to address the overdose crisis, we will use Medicaid enrollment, inpatient, outpatient, and pharmacy Transformed Analytic Files (TAF) from California from 2018-2022 to conduct an observational analogue of a stepped-wedge trial among 186 California EDs that implemented CA Bridge during this period (58% of all California EDs). We will evaluate both short- and longer- term clinical impacts of CA Bridge implementation among Medicaid patients with OUD, and sub-analyses will examine impacts on racial/ethnic and rural/urban disparities by examining these factors as potential effect moderators. This project’s specific aims are: Aim 1) To determine the impact of CA Bridge implementation on rates of MOUD initiation (within 3 days of index ED visits) among Medicaid patients presenting to the ED with OUD. Aim 2) To assess whether CA Bridge implementation is associated with increased utilization of outpatient behavioral health services (within 90 days of index visits) and continued MOUD use (up to 360 days after index visits) among Medicaid patients presenting with OUD. Aim 3) To evaluate whether CA Bridge implementation is associated with reduced risk of fatal and non-fatal overdose (up to 360 days after index visits) among Medicaid patients presenting with OUD. For each aim, we will examine CA Bridge impacts on racial/ethnic and rural/urban disparities. Study results will have national health policy implications, as federal and state policymakers seek effective ED-based strategies to reduce overdose deaths. EDs nationwide are implementing programs to respond to the opioid epidemic, including ~600 EDs that have already adopted CA Bridge protocols. This work will inform researchers, clinicians, and program administrators regarding the strengths and limitations of implemented programs emphasizing ED-initiated MOUD, enabling program adaptation to maximally reduce overdose risk in the Medicaid population.

NIH Research Projects · FY 2024 · 2024-09

PROJECT SUMMARY / ABSTRACT Alzheimer’s Disease (AD) is an incurable brain disorder which affects 1 in 10 individuals above the age of 65. With age, there is a progressive loss of neurons in the brain that becomes accelerated in the presence of AD pathology, resulting in cognitive decline. Although multiple pathological processes in the brain (e.g. inflammation, amyloid or tau) can cause neuronal loss, little is known about pathways that promote neuronal survival and repair. Data from our lab suggest that neuronal survival and repair pathways are regulated by a class of bioactive ‘pro-repair lipid mediators’ that are mostly bound/esterified to brain phospholipids. Unlike free lipid mediators, pro-repair mediators trapped in phospholipids are inactive and cannot repair the brain. In AD, there is a deficit in free pro-repair lipid mediators in the brain which could be caused by increased ‘trapping’ in phospholipids and other lipid pools. The main goal of this proposal is to understand whether neuronal loss in AD is caused by deficits in the supply of free pro-repair lipid mediators from brain esterified lipid pools. The central hypothesis is that in AD, neuronal damage and loss occur because of deficits in the supply of free pro-repair lipid mediators from esterified lipid pools. In Aim 1, we will use tracer studies to understand the time-course of changes in pro- repair lipid mediator turnover from esterified lipid pools in relation to neuronal loss, cognitive impairments and pathological markers of AD (e.g. inflammation) in a transgenic rat model of AD. In Aim 2, we will test whether repletion of esterified pro-repair lipid mediator pools in AD rats, confers neuroprotection and reverses behavioral (cognitive) impairments by increasing the supply of free pro-repair lipid mediators. Understanding whether the supply of free lipid mediators from esterified pools is defective in AD, paves the way for developing targeted therapies that can revive neuronal loss and cognitive impairments caused by the disease.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY/ABSTRACT Poverty and income inequality have wide-ranging and disproportionate effects on children and families living in marginalized, minoritized, and low-wealth communities, including environmental, social-emotional, and behavioral health sequela that elevate risk for, and racial/ethnic inequities in, community violence and harm. At the same time, limited but promising evidence suggests that strategies that influence structural and social determinants of health by enhancing economic opportunity and helping families avoid financial stress can prevent violence and promote well-being and intersectional racial equity beyond economic outcomes. The overarching goal of this project is therefore to evaluate whether, how, and for whom two of the largest anti- poverty public policies in the United States—the Earned Income Tax Credit (EITC) and Additional Child Tax Credit (ACTC)—affect the determinants, consequences, and prevention of multiple community violence-related outcomes among low-income families who are disproportionately affected by violence and its upstream structural and social causes. We will use a variety of analytic techniques, including difference-in-differences, the g-formula method for multiple causal mediation, and novel gap-closing estimands, along with data from the Future of Families and Child Wellbeing Study (FFCWS), a racially diverse longitudinal birth cohort study of structurally disadvantaged urban children and their families spanning tax years 1997-2021, to address the following three more specific aims: (1) to estimate the overall and sex- and race/ethnicity-specific associations of federal and state EITC and ACTC benefits received during childhood (ages 0-15) with community violence in adolescence (age 15) and young adulthood (age 22), including physical fighting, weapon use, and direct and indirect exposure to community violence; (2) to investigate the intermediate mechanisms through which the EITC and ACTC may impact community violence, including behavioral, consumption, and family and environmental stress-related processes; and (3) to identify how racial/ethnic inequities in exposure to and experiences of community violence would change if the availability and generosity of the EITC and ACTC were equalized across time and place or if selected preconditions of benefit eligibility such as employment and income minimums were removed. This research addresses Notice of Funding Opportunity (NOFO) Objective Three and multiple National Center for Injury Prevention and Control (NCIPC) Research Priorities, including cross-cutting and youth violence prevention research, as well as research to refine the concept, definition, and measurement of adverse childhood experiences to include structural and social conditions that elevate risk for community violence, including income and basic needs insecurities directly addressed in this project.

NIH Research Projects · FY 2025 · 2024-09

Exploring the Effectiveness of Housing Policy as a Structural Intervention to Reduce Community Violence: An Evaluation of Choice Neighborhoods and Source of Income Anti-Discrimination Laws Project Summary/Abstract The objective of the proposed study is to evaluate housing policy as a modifiable structural driver of community violence and violence disparities among youth and young adults. We propose to evaluate two distinct housing policies, each representing a different approach to addressing segregation and/or concentrated disadvantage. We hypothesize that these policies will have downstream preventive effects on youth community violence via their ameliorative effects on segregation and/or concentrated disadvantage, which are known causes of violence. This proposal is responsive to Objective Three of the RFA: effectiveness research to evaluate approaches that improve the social or structural conditions that contribute to community violence and racial and ethnic inequities in risk for community violence. It also addresses the National Center for Injury Prevention and Control’s research priority of youth violence. We will evaluate two policies: 1) the US Department of Housing and Urban Development’s Choice Neighborhoods program, which provides neighborhood revitalization grants to neighborhoods subject to historical disinvestment and with distressed public housing, and 2) source-of-income (SOI) anti-discrimination laws, which prevent landlords from discriminating against potential tenants that receive rental assistance via the Housing Choice Voucher program (formerly called Section 8). We will accomplish our study objective through the completion of the following specific aims: 1) to evaluate the effectiveness of Choice Neighborhoods and SOI anti-discrimination laws at reducing community violence among youth and young adults; 2) to evaluate the effectiveness of Choice Neighborhoods and SOI anti-discrimination laws at reducing racial and ethnic disparities in community violence among youth and young adults; and 3) to identify and quantify mediators of the relationship between Choice Neighborhoods and SOI anti-discrimination laws and community violence among youth and young adults. The Choice Neighborhoods evaluation will use a quasi-experimental design, staggered difference-in-differences, to estimate the average treatment effect associated with receiving a revitalization grant compared to not receiving a grant (among grant applicants). The SOI anti-discrimination law evaluation will be a serial cross-sectional study of approximately 80 cities using generalized estimating equations to estimate the association between having these laws and youth community violence (and disparities therein). Youth community violence will be measured as fatal and nonfatal assaultive injuries among people aged 10-34 years, measured with comprehensive hospitalization and vital statistics data. Sophisticated causal inference methods, including causal mediation analyses, will be used to minimize confounding bias and explore the mechanisms through which housing policies may influence violence. The proposed project promises to advance our understanding of the structural drivers of community violence among youth and young adults and will be of interest to policymakers and researchers in public health, criminology, and urban studies.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY A successful vaccine for systemic Salmonella infections will need to induce Th1 memory cells, but the tissue location and required functionality of these cells is poorly understood. Our preliminary data show that liver Tissue Resident Memory (TRM) CD4 T cells express higher levels of IL-18R and are more protective than the corresponding TRMs cells in the lamina propria. In this application, we will test, (i) whether IL-18R expression allows non-cognate responsiveness and robust TRM-mediated protection, and (ii) whether the use of a mRNA nanoparticle delivery system can induce this protective population in the liver of vaccinated mice.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY The widespread adoption of inaccurate and biased methods has impeded effective analysis and stymied comprehensive understanding of the composition and dynamics of the human virome. In this project we aim to develop innovative and novel laboratory techniques and computational methods to overcome the major challenges in identifying and characterizing human viruses. Our research team has successfully developed and deployed robust viromics methods for soil microbial communities, leading to a revolution in understanding of soil viral ecology. Preliminary data strongly indicate that these methods are also effective on human stool samples. Here, we will first optimize laboratory methods for recovery and quantification of RNA and DNA viruses from human stool (Aim 1). This aim directly addresses multiple specific interests described in the NOFO by developing techniques for 1) viral isolation and viral detection, 2) viral quantification, 3) viral enrichment for downstream sequencing, 4) eliminating environmental background and contaminating sequences, and 5) proper human sample procurement and storage. We have specific plans to complete this aim by leveraging our research team’s extensive experience in viromics, software development, and the human microbiome. Next, we aim to comparatively evaluate stool viromics techniques by applying them to a longitudinal human cohort (Aim 2). Here we will assess DNA and RNA viromics and other omics techniques for their ability to capture viral dynamics and develop a computational approach to translate the data generated from different methods to enable meta- analyses across studies. This directly addresses the specific interest to develop in silico methods to compare viromes across studies. We will complete this aim by leveraging our research team’s extensive experience developing, publishing, and maintaining user-friendly and highly used software programs. Finally, we aim to extend our technique’s applicability to diverse types of human samples, including those with low biomass (Aim 3). Priority sample types will be chosen in consultation with the full HVP Consortium. This work addresses the key technological and methodological challenges that are currently hindering robust interrogation of the constituents and functionality of the human virome.

NIH Research Projects · FY 2024 · 2024-09

Not Applicable no Abstract

NIH Research Projects · FY 2025 · 2024-09

Distractibility poses a significant public health concern for our youth, due to the seemingly never-ending barrage of visual and auditory stimulation in our real-life and digital environments. The influx of texts and social media alerts, traffic, and near peer discussions can interfere with their ability to sustain on-task attention. This challenge is further compounded by internal distractions such as mind wandering and ruminations. For youth, distractibility takes its heaviest toll in academic situations, whether in the classroom or when studying at home. However, traditional metrics of distractibility, from the clinic or laboratory, tend to be broad based or lack contextual information limiting their ability to predict real-life performance. We propose to use three innovative, state-of-the-art approaches to enhance the measurement of distractibility to better capture what youth experience in learning situations. We will apply a Research Domain of Criteria (RDoC) framework, with the goal of improving understanding of Attention in the RDoC Cognitive System Domain and how the Distractibility subfactor manifests in varying degrees across naturalistic learning contexts. We will study distractibility in neurotypical (NT) adolescents and youth with varying degrees of impairing distractibility, including those with diagnosable Attention-Deficit/Hyperactivity Disorder (ADHD). Our translational team from UC Davis and Bar Ilan University will assess distractibility, using different methods, across three naturalistic learning environments: 1) a Virtual Reality (VR) classroom using real academic tasks, while capturing eye-gaze and behavioral performance; 2) a Live Real classroom, using mobile EEG to measure neural processing and observing behavioral manifestations of distraction; and 3) throughout the course of students' real-life learning activities, both at school and during homework, using ecological momentary assessment (EMA) of attention. As the RDoC framework recommends, we are examining distractibility across multiple units of analysis including multi-informant (self, parent, teacher) behavioral ratings, self-report live ratings (EMA), behavioral performance, eye gaze, neural activity and a variety of functional measures related to learning and executive functioning. The UC Davis team will study adolescents recruited to represent a dimension of attentional functioning from NT through ADHD. The Bar Ilan research team is embedded in a high school and will recruit “natural cohorts” of typical high-school students (9th grade), representative of the general population. We will assess how our measures predict real-life functioning and distinct attentional profiles (subgroups) of attentional challenges using latent profile analyses within these heterogeneous samples. This innovative, translational and cross-cultural collaboration will greatly advance our understanding and measurement of distractibility in ecologically-relevant circumstances. Results will inform the development of measures for the clinic and laboratory and precision interventions to mitigate distractibility's adverse effects on youth's everyday functioning, bridging the translational gap between research, clinical practice, and educational activities.

NIH Research Projects · FY 2025 · 2024-09

Abstract One of the most remarkable properties of the brain is its ability to undergo adaptive modifications in response to changing environments. This experience-dependent plasticity is essential not only for the fine- tuning of developing circuits, but also for learning in adults. Advanced fluorescent labeling and imaging techniques have enabled direct visualization of the structural and functional reorganization of neuronal circuits during learning. Dendritic spines have been a major focus of these studies; spine gain or loss is associated with formation or elimination of neural circuit connections, and the enlargement or shrinkage of spines accompanies increases or decreases in the strength of synaptic connections. Notably, neurological and neurodegenerative disorders that result in cognitive dysfunction and disrupt learning are usually associated with changes in the density or morphology of dendritic spines. The long-term goal of this research proposal is to elucidate the molecular signaling mechanisms that regulate the growth, stabilization, and functional maturation of dendritic spines and their associated synapses during the activity-dependent synaptic plasticity that is associated with learning. To achieve this goal, we will use two-photon imaging and photostimulation techniques combined with genetically-encoded biosensors and fluorescence lifetime imaging to measure spatiotemporal signaling in neuronal dendrites, and molecular genetic, pharmacological, biochemical and proteomic techniques to identify key signaling pathways and complexes that regulate excitatory synapse plasticity. In Aim 1, we will delineate the unexpected role of the RhoGEF Ephexin5 and its downstream signaling pathways the activity-dependent spine growth and stabilization that is vital for learning and how these pathways are altered in cellular models for studying Alzheimer’s disease. In Aim 2, we will elucidate the novel non-enzymatic roles and interactions partners of CaMKII in nascent spine growth and stabilization as new circuit connections are established and we will define how these signaling pathways contribute to synaptic dysfunction in models for studying Alzheimer’s disease. Results from these experiments will rigorously address novel and unexpected molecular mechanisms of excitatory synapse growth and stabilization, thereby filling gaps in our current understanding of learning-associated neural circuit plasticity, with the ultimate goal to facilitate the development of therapeutics for human diseases associated with intellectual disability.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Gastric cancer (GC) has a high mortality rate in Latinos. This is likely the result of multi-level social determinants of health and population-specific factors. Our recent cancer registry-based study showed that Latinos have high rates of poor prognosis diffuse GCs. Compared to intestinal-type tumors, Latinos with diffuse tumors had ~50% lower 5-year survival. In addition to the histological classification, TCGA described four GC molecular subtypes, including the genomically stable (GS) subtype, characterized by diffuse histology, low mutation and copy number alteration rates and a high frequency of “undruggable” CDH1 and RHOA mutations. GS tumors are chemotherapy-resistant, immunologically “cold,” and have the worst prognosis. Interestingly, we recently showed that ~50% of all Latino patients have GS tumors, a fraction that is >3-fold higher than in Asians and Whites. Hence, our studies suggest that Latinos are enriched with poor prognosis GC histological and molecular subtypes, partly explaining GC disparities. Given the high GS prevalence in Latinos, we obtained paired tumor- normal reduced representation bisulfite sequencing (RRBS) data from 15 Latino patients and re-analyzed TCGA methylation data to carry a preliminary GS epigenome analysis. We found that GS tumors, compared to other subtypes, are enriched with differentially methylated genes (DMGs) in key pathways such as WNT, TGF-beta and PI3K/AKT signaling, which may explain their aggressiveness and chemoresistance. Our analyses also highlighted key limitations of existing publicly available GS epigenome data. For example, TCGA lacked Latino samples and profiled primarily tumor-only samples using sub-optimal methods as we found that RRBS identified many methylated regions that were missing in TGCA methylation arrays and which appeared to be GS-tumor, and possibly Latino-specific. Our preliminary studies therefore highlighted several research gaps that will be addressed in the present application. The objectives of the present application are to advance our understanding of GS tumor biology using epigenomic and functional genomic approaches. To this end, we will leverage our expertise in cancer biology, health disparities, patient-derived modeling, preclinical studies, and genome engineering. Our hypothesis is that Latino GS tumorigenesis follows unique biological pathways, some which may be amenable to therapeutic development. In Aim 1, we will characterize the epigenome of 100 Latino GS tumors using RRBS. Aim 2 will investigate GS tumorigenesis using ethnic-appropriate Latino gastric organoids and isogenic modeling for CDH1 and RHOA. In Aim 3, we will perform a loss of function screen that will be used to identify synthetically lethal associations in CDH1- and RHOA-mutant GS cell lines, some of that maybe amenable to molecularly guided therapies. Our study will significantly advance our understanding of GS tumors' biology and therapeutic vulnerabilities. As GS tumors are likely drivers of higher mortality rates in Latinos, our study will also significantly advance cancer health equity in the country.

NIH Research Projects · FY 2025 · 2024-09

Project Summary/ Abstract Our long-term objective is to improve the efficacy and safety of liver cancer transarterial embolization through new computational tools that enable the development of new personalized treatment strategies. The continued rising mortality and incidence make research on improving liver cancer management essential. Transarterial embolization is used to obstruct the tumor blood flow (TAE) and deliver localized radiation (yttrium-90 radioembolization 90Y TARE) or chemotherapy (chemoembolization TACE). 90Y TARE counted for more than 10,000 interventions in the US in 2022. Demonstrated benefits for patients include increased time to progression but moderate improvement of overall survival, in part because it is only used as second or third line treatment on advanced cancers. Recent 90Y TARE clinical trials showed a correlation between the tumor dose and patient outcome, indicating that robust and precise targeting must be pursued. Targeting is however complex, highly patient-dependent, and difficult to plan with current imaging techniques. This leads physicians to underdose 90Y TARE to limit liver toxicity, missing the tumoricidal dose of ~50 in 80% of patients. TAE and TACE are performed with a fixed dosage and also frequently fail: post treatment imaging shows residual blood flow in ~70% of tumors treated with TACE, indicative of incomplete occlusion of the tumor blood supply. If the efficacy and safety profile of TAE were improved through better planning, it could have a much higher impact on patient outcome, helping patients at earlier stages and reducing mortality. Tools to develop such treatment planning currently lack robustness and accuracy. This U01 proposal follows the concept of a liver digital twin to develop an in silico platform to optimize liver transarterial embolization. Tumor targeting is achieved by selecting the injection points and dosage; it remains mostly empirical based on pretreatment vascular imaging with limited robustness. We propose a novel personalized treatment planning using a liver digital twin that builds on our previous work developing CFDose, a simulation pipeline based on computational fluid dynamics and physics modeling informed with patient CT images. CFDose predicts the liver dose through blood flow simulation using standard-of-care imaging, requiring no changes to the clinical workflow. We will use it as a building block to develop patient-specific in silico optimization of TAE, TARE, and TACE. The algorithm will sample the injection point and dosage, simulate the dose or drug concentration distribution (activating the liver model multiple times), and compare it with the physician’s target. The project will develop the patient-specific virtual liver model to simulate the distribution, will accelerate the simulation with artificial intelligence (GANs), and will integrate the liver model into an optimization algorithm. The virtual liver model acts a digital twin of the patient’s liver to assist TAE planning. There is a dire need for predictive multiphysics and multiscale liver models that include blood flow, a major component of liver disease. Our digital twin liver can fill this gap for liver cancer.

NIH Research Projects · FY 2025 · 2024-09

Project Summary Scientific teams led by Prof. Oliver Fiehn (UC Davis), Prof. Charles Evans (University of Michigan) and Dr. Tom Metz (Pacific Northwest National Laboratory) will develop and validate a unified, cloud-based data processing workflow and database for high resolution LC-MS/MS metabolomics and lipidomics data. This new database, LC-BinBase, will serve as cornerstone to harmonize and standardize metabolomics data reports. Through both experimental and computational robustness tests, we will show that different metabolomics laboratories can generate consensus data sets if the same set of data acquisition methods are used, even if instruments from different vendors are used. This work will lead the way for next-generation metabolomics, towards faster, more reproducible and robust data processing that leads to standardized data reports and improved interpretability for biomedical researchers. To this end, we will develop algorithms to apply LC-BinBase with calculated metabolite annotation confidence scores for both hydrophilic interaction- and reversed phase chromatography, and for both QTOF and orbital ion trap high resolution mass spectrometers. These confidence scores will be calculated from deviations of probability distributions of experimental and predicted retention times, accurate masses, MS/MS entropy similarity scores and ion mobility data. We will validate the usability of LC-BinBase reports for biomedical researchers by interlaboratory comparison studies on diverse sets of mouse organs, plus different cell types and biofluids. Data usability will be improved by a unified compound metadata list for all annotated metabolites. We will organize events and workshops to invite the scientific community to beta-test LC-BinBase.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Robust daily biological rhythms over the 24-hour (h) day-night cycles are key hallmarks of animal healthspan and are strongly regulated by circadian clocks. Circadian clocks are cell-autonomous, endogenous molecular timers present in the brain and peripheral organs that enable animals to adapt to daily changes in their environment. Clock-controlled outputs are all-encompassing and clock disruption is associated with a wide range of pathologies and chronic diseases. While the brain clock is synchronized to external environment via photic cues from light-dark cycles, peripheral clocks in major organs are entrained and synchronized by metabolic signals mediated primarily via food intake that are regulated by the brain clock. This coupled brain and peripheral clock system promotes internal synchrony, maintaining balance between metabolism and energy use. Given the importance of metabolic signals in regulating body clocks, it is critical to understand mechanisms underlying metabolic regulation of daily biological rhythms. The overall goal of this project is to investigate post-translational mechanisms that mediate metabolic regulation of time-of-day protein functions to orchestrate daily rhythms. Efforts to understand the underpinnings of circadian clocks and their control over daily rhythms have long focused on regulation at the transcriptional level. However, recent studies have demonstrably confirmed the importance of post-translational modifications (PTMs) in shaping robust daily rhythms, often bypassing regulation at the gene expression level. We recently established that metabolic signals from feeding-fasting cycles drive robust daily rhythms of global O-GlcNAcylation in Drosophila and in mouse peripheral tissues. O-GlcNAcylation is a nutrient-sensitive PTM that interacts extensively with phosphorylation to regulate protein structure and function as both PTMs modify serine and threonine residues. We will test the hypothesis that rhythmic O-GlcNAcylation and phosphorylation work in conjunction to regulate daily rhythms of protein activities. We further test the hypothesis that altering timing of metabolic input by mistimed feeding will remodel the O-GlcNAcome, phosphoproteome, and their interactions, resulting in potential disruption of peripheral clock functions. To date, there have only been a handful of studies investigating rhythmic O-GlcNAcylation and the consequences of its disruption. This project is designed to address this significant knowledge gap. In Aim 1, we will identify proteins that are rhythmically modified by O-GlcNAcylation and phosphorylation in key mammalian organs and investigate whether and to what extent rhythmic PTM profiles are sensitive to timing of metabolic input. In Aim 2, we will incorporate proteomics data generated from this project into O-GlcNAc Atlas, a searchable database with a web interface constructed by our collaborator Dr. Junfeng Ma, to enable user-friendly data discovery. This R21 project will provide new insights into the regulation of daily biological rhythms by nutrient-sensitive PTMs and catalyze functional characterization of nutrient-sensitive molecular pathways in a rhythmic biology framework.

NIH Research Projects · FY 2025 · 2024-09

We propose to establish the “UC Davis Intentional Genomic Alteration (IGA) Innovation Center” focused on research on IGAs in major livestock species to advance the use of gene editing technologies in food animals, while generating and sharing both phenotypic and bioinformatic data to support a science-based approach to the regulation of IGAs in food animals. UC Davis has long been a leader in applying genetic technologies to farm animal species and we are uniquely positioned to address issues surrounding the use of gene editing in animals destined for the food chain due to the depth and breadth of extant food animals (cattle, pigs, sheep, and goats) with IGAs we have generated, and the pipeline we have planned for the future. These animals have been produced for both agricultural and biomedical purposes over the past 20 years, with gene edited animals predominating in the past 5 years. This inventory includes genetically engineered and gene-edited knockout and knock-in animals resulting from both microinjection and electroporation, some of which have multiple generations of offspring. The specific aims of this Cooperative Agreement are: Aim 1: To develop a gold standard workflow for assessing on- and off-target events as a result of gene editing. Whole genome sequencing (WGS), in vitro and in silico approaches to detect on- and off-target events will be compared to establish a strategy that will account for natural sequence variability, sequencing depth and bioinformatics workflows to ensure accurate identification of on- and off-target changes in the genome. Aim 2: To document the genotypic and phenotypic durability of IGAs across generations and species. Genotypic durability of on- and off-target events will be documented in gene edited cattle, pigs, and sheep and, bovine embryonic stem cells (bESCs) and phenotypic durability assessed including compiling information on known variation in nutrient profiles of products derived from food animals to help inform design of experiments to explicitly evaluate alterations in product composition. Aim 3: To assess the reproducibility of various gene editing platforms including prime editing in terms of efficacy of editing and presence of off-target cutting in different cell types. We anticipate sharing the materials and data we produce with FDA scientific or program staff and coordinating project activities with the FDA to provide evidence to address regulatory questions to help advance the safe use of gene editing to improve the sustainability of animal agriculture, and facilitate more FDA-regulated products coming to market.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Excitatory ionotropic synapses and their associated dendritic spines play critical roles in fundamental information processing within the brain. The development and morphology of these synapses are highly functionally relevant; previous studies have established that patients with many different neurodevelopmental, neurodegenerative, and neuropsychiatric conditions are clinically defined by synaptopathies. Synaptopathies, or disease at the level of the synapse, includes inappropriate loss of synapses and spines, enhanced or lowered synapse and spine development, and aberrations to the synaptic structure that leads to dysfunctional signaling. The Brain-specific angiogenesis inhibitor (BAI) subfamily of neuronal adhesion G-protein coupled receptors (aGPCRs) are a three-member postsynaptic family of receptors predicted to form trans-synaptic complexes to direct synaptogenesis and synapse structural development. BAI2 is the least studied of these proteins, with no established role in neuronal or synaptic development. BAI2 also appears to be the most functionally non-redundant member of the BAI family. Though whole exome data from human patients with autism spectrum disorder, schizophrenia, and bipolar disorder suggests all BAI proteins are implicated in these conditions, BAI2 does not bind the same presynaptic proteins as BAI1 and BAI3. Furthermore, a gain-of- function mutation to BAI2 is the putative cause of a rare spastic paraparesis condition in humans, and loss-of- function mutations are associated with hyperactive behavior in mice. Addressing the fundamental role and molecular mechanism of BAI2 thus can help us understand both basic synapse development, and potentially inform future studies into treatments of psychiatric and central nervous system-derived motor disorders. To this end, my data on BAI2 suggests that the protein localizes to the PSD and promotes both pre- and postsynaptic development. I propose to further define the role of BAI2 in synapse and spine development by delineating the functional domains that regulate synapse development (Aim 1.1), quantifying nanostructural changes to synaptic structures (Aim 1.2), and describing functional deficits (Aim 1.3) induced by loss of BAI2. In the future, I plan to pursue a postdoctoral position investigating real-time changes to excitatory and inhibitory synaptic nanodomains and signaling in baseline, plasticity, and disease conditions (Aim 2).

NIH Research Projects · FY 2024 · 2024-09

PROJECT SUMMARY Hepatocellular carcinoma (HCC) is the most common type of liver cancer in adults in which most cases develop in patients with liver cirrhosis. The incidence and mortality of HCC is rising and showing widening disparities, with the Latinx population having the greatest increase over the last decade. Latinxs represent 19% of the total U.S. population, comprise the largest racial/ethnic group in California (CA, 40%), and are notably underrepresented in current research into biomarkers for HCC. Notably, HCC in U.S. born Latinxs from Mexico is double that of Mexican-born individuals, underscoring the importance of social, behavioral, and environmental risk factors on hepatocarcinogenesis. In our preliminary research using the Microbiome, Microbial Markers, and Liver Disease (M3LD) Study, a multicenter prospective cohort of individuals with liver cirrhosis recruited across CA, we published the first-in-human evidence showing a role for the gut-liver axis in HCC risk. We identified a duodenal microbe (Alloprevotella), circulating metabolites (methionine and methionine sulfoxide), and bile acid (taurocholic acid) that were associated with subsequent diagnosis of HCC. We found a Latinx ethnicity-specific microbiome composition in participants with cirrhosis, and we showed that dietary factors previously associated with reduced HCC risk (healthy eating index, coffee, fiber, and protein) were associated with Latinx ethnicity and significant microbial differences in participants with cirrhosis at risk of HCC. Based on these preliminary results, this study proposes to expand the M3LD cohort by enrolling ~1000 participants with liver cirrhosis enriching for the Latinx population, who will be followed prospectively for HCC development. We will collect duodenal biopsy and blood specimens, clinical data, and epidemiological data. We will characterize the duodenal barrier and identify novel bacteria and glycans, and probe for microbial- related serum immune markers and metabolites. The overall goal is to apply a rigorous experimental design that will reveal mechanisms that influence HCC risk in the Latinx population, ultimately leading to the identification of novel biomarkers for risk assessment and targets for HCC prevention, and a disparity reduction.